Significant progress was made in understanding the neurobiology of the club drug Ecstasy (i.e., MDMA) and with developing possible treatment approaches for human users. First, we provided evidence that locomotor stimulant properties of MDMA are mediated by increases in synaptic levels of dopamine and serotonin (5-HT) in critical brain areas, including the nucleus accumbens. It is well known that accumbens dopamine is involved in the hyperactivity caused by stimulant drugs, and our recent findings implicate 5-HT in specific repetitive behaviors (i.e. stereotypy) produced by MDMA. In a second study, we showed that high-dose binge exposure to MDMA causes tolerance to locomotor and neuroendocrine effects of the drug in rats. The observed tolerance was associated with depletion of forebrain 5-HT and impaired ability to release 5-HT from neurons. These data from rats suggest that tolerance development in human Ecstasy users could be related to depletion of brain 5-HT and subsequent serotonergic dysfunction. MDMA tolerance often results in dangerous dose escalation in human users who attempt to recapture the intense quality of the initial MDMA experience. Finally, in a third study, we showed that treatment with the 5-HT precursor, L-5-hydroxytryptophan (5-HTP) can restore the depletion of 5-HT produced by MDMA in rats. As such, 5-HTP might be an important adjunct for the treatment of Ecstasy users who display 5-HT-related disorders during drug withdrawal (i.e., depression).